Many brain disorders show a strong gender bias in prevalence, suggesting that normal sex differences in the brain may contribute to their etiology. The broad goal of this proposal is to understand the neural mechanisms underlying sex differences in the brain, in order to elucidate how sex-specific development can produce a brain that is susceptible to specific brain disorders. Our laboratory has established that sexual differentiation of the preoptic area (POA), a key brain region involved in reproductive behavior, is regulated by the lipid molecule, prostaglandin E2. Prostaglandins are associated with proinflammatory signaling in the brain in response to injury or infection, however they also play a key role in normal synaptic development in the POA. We propose to investigate the role that microglial cells play in sexually differentiating the POA, as microglial cells are both a source of and responsive to prostaglandins in the context of brain inflammation and injury. Microglia, the primary immunocompetent cells in the brain, are also in a predominantly activated state in the developing brain, suggesting they contribute to normal brain development and plasticity. Two specific aims will test several hypotheses by determining 1) whether there are sex differences in microglial cell number, activity, or cytokine signaling in the developing preoptic area and 2) whether neonatal microglial inhibition disrupts the morphological sexual differentiation of the preoptic area and resulting sex-specific behaviors. These experiments will give insight into the interaction between the nervous, endocrine, and immune systems to produce sex-specific brain development. PUBLIC HEALTH RELEVANCE: A major predictor of an individual's susceptibility to any given neurological disorder is their sex: Males show much higher rates of autism spectrum disorders, ADHD, and epilepsy, whereas females show higher rates of migraine headaches, chronic pain, depression, and multiple sclerosis. Brain inflammation early in life is a risk factor for developing a neurological disorder. Studying the basic mechanisms through which sex differences in the brain are established and how inflammatory signaling contributes to brain development will provide insight into how sex-specific brain development can lead to vulnerability to brain abnormality and disorders.